Crtap function during skeletal homeostasis

骨骼稳态过程中的 Crtap 功能

• 批准号: 7053382
• 负责人: ROY MORELLO
• 金额: $ 7.32万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-26 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7053382
• 关键词: bone development; cartilage; cartilage development; collagen; computed axial tomography; genetic regulation; histology; homeostasis; laboratory mouse; osteocytes; osteoporosis; phenotype; protein structure function; tissue /cell culture

DESCRIPTION (provided by applicant): Osteoporosis is a common bone disease characterized by low bone mass and deterioration in the microarchitecture, with a consequent increase in bone fragility and susceptibility to fractures. Primary osteoporosis can be due to attainment of lower peak bone mass during puberty and early adulthood, and/or to an unbalance between bone formation and bone resorption. Genetic factors are a primary determinant of this and animal models have been extremely helpful for identifying new genes and pathways that play a role in this process. This proposal focuses on a novel gene that could be important in a crucial pathway that regulates bone formation, the synthesis of fibrillar collagens. In an effort to identify new gene in the regulation of cartilage and bone formation, we previously identified a gene by differential screening of in vitro cultured chondrocytes and named it Crtap (Cartilage Associated Protein). To understand its in vivo function, we generated a null mutant mouse for the Crtap gene. Our initial observations show that the Crtap null mice develop a severe early onset osteoporosis and age-related kyphosis. To comprehend the functional characteristics of the Crtap gene we propose to systematically analyze the consequences of Crtap loss of function during skeletal formation and homeostasis. First, histological, histomorphometric, micro-CT and biochemical analyses will be performed to better characterize the skeletal phenotype of the Crtap-/- mice and hence determine whether the bone defect is secondary to dysregulated bone formation and/or bone resorption. Second, we will perform functional in vitro studies on primary cultures of osteoblasts and osteoclasts in order to identify cell-autonomous defects. These initial experiments are expected to begin elucidating the function of the Crtap gene during bone formation and homeostasis and its role in the pathogenesis of osteoporosis. Importantly, they may identify a new regulator of collagen post-translational modification, folding, assembly or secretion.

描述（由申请人提供）： 骨质疏松症是一种常见的骨骼疾病，其特征是骨骼质量低和微体系结构中的恶化，因此骨骼脆弱性和对骨折的敏感性的增加。原发性骨质疏松症可能是由于青春期和成年初期达到较低的峰值骨量以及/或骨形成和骨吸收之间的不平衡所致。遗传因素是这种主要决定因素，动物模型对确定在此过程中起作用的新基因和途径非常有帮助。该提案的重点是一种新的基因，该基因在调节骨形成的关键途径中很重要，即纤维胶原的合成。为了在调节软骨和骨形成中鉴定新基因，我们先前通过鉴定体外培养的软骨细胞的差异筛选鉴定了一个基因，并将其命名为CRTAP（软骨相关的蛋白质）。为了了解其体内功能，我们为CRTAP基因生成了一个无突变小鼠。我们的最初观察结果表明，CRTAP无效小鼠会出现严重的早期骨质疏松症和与年龄相关的脑膜病。为了理解CRTAP基因的功能特征，我们建议系统地分析骨骼形成和稳态期间CRTAP功能丧失的后果。首先，将进行组织学，组织形态计量学，微CT和生化分析，以更好地表征CRTAP - / - 小鼠的骨骼表型，因此确定骨缺损是否是继发骨形成和/或骨吸收功能失调的次数。其次，我们将对成骨细胞和破骨细胞的原代培养物进行功能性研究，以鉴定细胞自主缺陷。预计这些最初的实验将开始阐明骨形成和稳态期间CRTAP基因的功能及其在骨质疏松症的发病机理中的作用。重要的是，他们可以确定胶原蛋白后翻译，折叠，装配或分泌的新调节剂。